Lecture 24/25: Cholesterol, Lipoproteins

Question 1

Statins

Answer 1

Drugs that lower blood cholesterol

Question 2

Cholesterol roles

Answer 2

Membrane fluidity, fat digestion (bile acids), steroid hormones; very hydrophobic w/ 4 ring structure

Question 3

Familial Hypercholesterolemia (FH)

Answer 3

Major type: LDLR mutation. Elevated plasma cholesterol + LDL (accelerates atherosclerosis development), cholesterol deposits on tendons/arteries in homozyg.

Question 4

Plasma lipoproteins

Answer 4

Particles that carry lipids at high concentration:
1. Chylomicrons
2. VLDLs
3. IDL
4. LDL
5. HDL
Larger = lower density cholesterol

Question 5

Cholesterol sources

Answer 5

Synthesized primarily in liver cytoplasm + ER; also small part from diet

Question 6

Committed step of cholesterol biosynthesis

Answer 6

HMG-CoA reductase -> irreversible reduction to mevalonate; rate-controlling, ER membrane anchored

Question 7

Acyl-CoA Cholesterol Acyltransferase (ACAT)

Answer 7

Intracellular ER enzyme; esterifies cholesterol for storage/transport. Free cholesterol is found in membranes ONLY

Question 8

Regulation of cholesterol biosynthesis via gene expression

Answer 8

1. SREBP-SCAP proteins on ER membrane move to Golgi
2. SREBP cleavage releases DNA binding domain
3. DNA binding domain binds to Sterol Regulatory Elements (SREs) as transcrip. factor, upregulating gene expression

High cholesterol leads SCAP to bind membrane Insig, leading to ER retention

Question 9

Hormonal regulation of HMG-CoA expression

Answer 9

Insulin, thyroxine in fed state signal high acetyl-CoA leading to upregulation

Glucagon, glucocorticoids downregulate HMG-CoA reductase

Question 10

Statin regulation of HMG-CoA reductase

Answer 10

Statins are reversible, competitive inhibitors of HMG-CoA reductase, lowering cell. cholesterol synth. thus promoting cholesterol uptake from blood.

Question 11

Cholesterol degradation

Answer 11

From liver:
1. Secreted into bile
2. Converted into bile acids

Question 12

Plasma lipoprotein structure

Answer 12

Spherical shell comprised of phospholipids, free cholesterol, apolipoproteins

Core of TAGs/CEs; less dense = more TAGs

Question 13

Chylomicrons

Answer 13

Signature Apo B-48 (also E, C-2)
Largest, least dense; deliver dietary TAGs to cells
Carry exogenous (dietary) lipids

Question 14

Absorption of dietary fat

Answer 14

Digestion and solubilization of TAGs via pancreatic lipase + bile salts -> micelles for uptake

Question 15

Lipoprotein lipase

Answer 15

Receptor on endothelial cells for cellular uptake of TAGs from chylomicrons; requires Apo C-2

Question 16

Chylomicron interaction with HDLs

Answer 16

Collision of HDL/chylomicrons -> surface Apo exchange; chylomicron -> remnant

Question 17

2 fates of Remnant plasma lipoproteins

Answer 17

1. Apo E retained -> liver uptake via Remnant receptor
2. Apo E loss to HDLs -> new nascent HDL disc

Question 18

VLDL particles

Answer 18

Only produced in liver, contain endogenous (non-dietary) lipids.
Signature Apo B-100, also Apo C-2, E

Question 19

Conversion of VLDLs to LDLs

Answer 19

VLDL TAG uptake via LPL -> IDL; loss of Apo E to HDLs -> LDLs

Question 20

LDLs

Answer 20

High cholesterol:TAG ratio; only has Apo B-100.

Question 21

LDL receptor pathway

Answer 21

1. LDL binds LDLR localized to clathrin-coated pits
2. LDL internalized within pit
3. Endocytotic vesicles fuse with primary lysosomes
4. Lysosomal lipases, esterases degrade TAGs, cholesteryl esters
5. LDLRs recycled back to plasma membrane or degraded

Question 22

Roles of free cholesterol leaving lysosome

Answer 22

1. Suppress HMG-CoA reductase
2. Increase ACAT
3. Decrease surface LDLRs

Question 23

HDL

Answer 23

Signature Apo A-1, comes from nascent HDL discs

Question 24

Nascent HDL discs

Answer 24

Made directly from liver, intestine, chylomicron remnants.
Spherical HDL precursor; substrate for LCAT, req. Apo A1

Question 25

HDL maturation

Answer 25

Disc picks up free cholesterol via LCAT (esterifies + packs) in plasma. Free cholesterol from extrahepatic tissues (e.g. macrophages); ABCA1, SRB1, ABCG1 transfer cholesterol to HDL to be brought back to liver. Can also exchange CE from HDL to other lipoproteins via CETP

Question 26

Cholesteryl Ester Transfer Protein

Answer 26

Swaps CE for TG from HDLs to other lipoproteins; results in more CE in LDLs so more circulating cholesterol

Question 27

Atherosclerosis pathogenesis

Answer 27

1. Init. injury -> endothelial dysfunction 2. LDL accumulates within intima and becomes oxidized 3. Oxidized LDL triggers endothelial cytokine secretion, recruiting + activating macrophages 4. Macrophages engulf ox. LDLs -> foam cells and recruit smooth muscle from media 5. Further ox. LDL digestion -> creation of fatty streak, sm. muscle secretes fibers to form fibrous cap. Rupture can lead to a thrombus

Question 28

HDL roles

Answer 28

1. Promote LDL cholesterol efflux from macrophage (ABCA1) 2. Promote oxidized LDL efflux from macrophages (ABCG1) 3. Inhib LDL oxid. 4. Inhib vascular inflammation, promote endothelial repair

Question 29

Cholestyramine

Answer 29

Bile salt sequestrant, increases bile salt excretion/inhibs reabsorption resulting in increased cholesterol consumption to lower serum cholesterol (upreg. LDLR, HMG CoA reduct.)

Question 30

How do oats reduce cholesterol?

Answer 30

Thickening of digested food results in less cholesterol uptake. Also binds + sequesters bile acids.

Question 31

PCSK9 inhibitor

Answer 31

Works with statins to further increase LDLR upregulation due to low cellular cholesterol, further promoting uptake of cholesterol from blood. Blocks LDLR protease, promoting recycling.

Question 32

Effect of decreased intestinal cholesterol uptake

Answer 32

1. Decreased CE in chylomicrons 2. Decreased CE return to liver via remnant 3. Decreased hepatic cholesterol stores 4. Decreased VLDL production 5. Increased LDLRs -> decreased circulating LDL